We are interested in the role of endogenous opiate peptides, called endorphins, in central nervous system functioning in general and in mental illness in particular. Much of our work has centered around FK 33-824, a synthetic enkephalin analogue which can be administered parenterally and orally and hence may be of use clinically. Animal studies have included demonstration of FK 33-824 inhibition of conditioned avoidance responding in rats and blockade of anxiety behavior and increase in serum prolactin in monkeys. These results suggest an interaction of FK 33-824 with brain dopamine and norepinephrine systems and possible antipsychotic and antianxiety properties in man. Clinical trials of FK 33-824 are planned. A controlled trial of the morphine like compound methadone in affective illness and schizophrenia is in its early stages. Also, the Branch is participating in collaborative double-blind controlled trials of beta-endorphin and of the opiate antagonist naloxone. We find little or no effect of naloxone in mania.